(1H-azol-1-ylmethyl)substituted quinoline derivatives

ABSTRACT

(1H-azol-1-ylmethyl)substituted quinoline derivatives, compositions containing the same, and methods of treating mammals suffering from disorders which are characterized by an increased proliferation and/or abnormal differentiation of epithelial tissues.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division of application Ser. No. 08/131,817, filed Oct. 5,1993, now U.S. Pat. No. 5,441,954, which in turn was a division ofapplication Ser. No. 07/973,871, filed Nov. 10, 1992, now U.S. Pat. No.5,268,380, which in turn was a division of application Ser. No.07/704,746, filed May 23, 1991, now U.S. Pat. No. 5,185,346, which was acontinuation-in-part of application Ser. No. 07/434,205, filed Nov. 13,1989, now abandoned.

BACKGROUND OF THE INVENTION

In U.S. Pat. No. 4,859,684 there are described (1H-azol-1-ylmethyl)substituted benzimidazole derivatives which compounds are useful asandrogenic hormone biosynthesis inhibitors. The compounds of the presentinvention differ from the cited art compounds by the fact that theycontain a quinoline or quinolinone moiety in place of an benzimidazolemoiety. U.S. Pat. No. 4,792,561 discloses carbostyril derivatives havingcombined thromboxane synthetase and cyclic-AMP phosphodiesteraseinhibiting properties. Some compounds of the latter patent and the novelcompounds of the present invention have now been found to suppress theplasma elimination of retinoic acids. Further, some of said compoundsalso inhibit the formation of androgens from progestines and/or inhibitthe action of the enzyme complex aromatase which catalyses the formationof estrogens from androgenic steroids in mammals.

DESCRIPTION OF THE INVENTION

The present invention is concerned with compounds of formula: ##STR1##the pharmaceutically acceptable acid addition salts thereof and thestereochemically isomeric forms thereof, wherein:

--X¹ ═X² -- represents a bivalent radical of formula

    --CH═CH--                                              (x),

    --CH═N--                                               (y),

    or

    --N═CH--                                               (z);

R represents hydrogen or C₁₋₆ alkyl;

Y represents hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, Ar¹, Ar² --C₁₋₆alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; and

Z represents a radical of formula ##STR2## wherein R¹, R⁴ and R¹⁰ eachindependently represent hydrogen, C₁₋₆ alkyl or Ar² --C₁₋₆ alkyl;

R², R⁵, R⁸ and R¹² each independently represent hydrogen, C₁₋₆ alkyl orAr² ;

R³, R⁶ and R¹¹ each independently represent hydrogen or C₁₋₆ alkyl; and

R⁷ and R⁹ each independently represent hydrogen, C₁₋₆ alkyl, C₁₋₆alkyloxy, halo, amino, or mono or di-(C₁₋₆ alkyl)amino; wherein in theforegoing:

Ar¹ represents phenyl, substituted phenyl, naphthalenyl, pyridinyl,imidazolyl, triazolyl, thienyl, furanyl or thiazolyl and Ar² representsphenyl or substituted phenyl; wherein said substituted phenyl in Ar¹ orAr² represents phenyl substituted with 1, 2 or 3 substituents eachindependently selected from the group consisting of halo, hydroxy,trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, cyano, amino, mono- anddi(C₁₋₆ alkyl)amino, nitro, carboxyl, formyl and C₁₋₆ alkyloxycarbonyl.

Novel compounds within the present invention are those compounds offormula (I) as defined hereinabove, provided that when (1) --X¹ ═X² --represents a bivalent radical of formula --CH═CH--, (2) R representshydrogen, (3) Z represents a radical of formula (a-1) or (a-2), and (4)R¹, R², R³, R⁴, R⁵ and R⁶ all represent hydrogen, then Y is other thanhydrogen, C₁₋₁₀ alkyl, Ar¹ or Ar² --C₁₋₆ alkyl.

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo; the term "C₁₋₆ alkyl" defines straight andbranched chain, saturated hydrocarbon radicals having from 1 to 6 carbonatoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and thelike; "C₁₋₁₀ alkyl" defines the higher homologs of "C₁₋₆ alkyl"containing 1-10 carbon atoms; the term "C₃₋₇ cycloalkyl" is generic tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; "C₂₋₆alkenyl" defines straight and branched chain hydrocarbon radicalscontaining one double bond having from 2 to 6 carbon atoms such as, forexample, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl and the like; "C₂₋₆ alkynyl" definesstraight and branched chain hydrocarbon radicals containing one triplebond and having from 2 to 6 carbon atoms such as, for example,2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl andthe like.

It is to be understood that the ##STR3## may be substituted on eitherthe 5, 6, 7 or 8 position of the bicyclic ring system, the 6 or 7position being preferred, the 6 position being most perferred.

Further it should be noted that the compounds of formula (I) wherein Zis a radical of formula (a-1) are denoted as compounds of formula(1-a-1), compounds of formula (a-2) are denoted as compounds of formula(I-a-2), compounds of formula (a-3) are denoted as compounds of formula(I-a-3) and compounds of formula (a-4) are denoted as compounds offormula (I-a-4).

The acid addition salts as mentioned hereinabove are meant to comprisethe therapeutically active non-toxic acid addition salt forms which thecompounds of formula (I) are able to form. The latter can convenientlybe obtained by treating the base form with appropriate acids such as,for example, inorganic acids, such as hydrohalic acid, e.g.hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid,phosphoric acid and the like; or organic acids such as, for example,acetic, hydroxyacetic, propanoic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be convened by treatment with alkali intothe free base form. The term acid addition salt also comprises thehydrates and solvent addition forms which the compounds of formula (I)are able to form. Examples of such forms are e.g. hydrates, alcoholatesand the like.

From formula (I) it is evident that the compounds of this invention mayhave several asymmetric carbon atoms in their structure. Pure isomericforms of the compounds of formula (I)can be separated from the mixtureby conventional separation methods. Preferably, if a specificstereoisomer is desired, said compound will be synthesized bystereoselective methods of preparation. These methods willadvantageously employ enantiomerically pure starting materials.

Further it is evident that the compounds of formula (I) may also containin their structure a tautomeric system and consequently these compoundscan be present in each of their tautomeric forms.

Particular compounds of the present invention are those compounds offormula (I) wherein R is hydrogen; and/or Y is hydrogen, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, substituted phenyl, pyridinyl, imidazolyl orthienyl; and/or Z is a radical of formula (a-1), (a-2), (a-3) or (a-4)wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R¹⁰, R¹¹ and R¹² each independentlyare hydrogen or C₁₋₄ alkyl, and R⁷ and R⁹ each independently arehydrogen, C₁₋₄ alkyl, C₁₋₄ alkyloxy or halo.

More particular compounds are those particular compounds wherein --X¹═X² -- is a radical having the formula (x) or (y); and Y is hydrogen,C₁₋₄ alkyl, cyclopropyl, cyclopentyl, cyclohexyl, imidazolyl, pyridinyl,thienyl or phenyl optionally substituted with one or two substituentseach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy andtrifluoromethyl.

Among the compounds of the aforementioned subgroups special emphases isput on compounds of formula (I) wherein Z is a radical of formula (a-1)wherein R¹ and R² are hydrogen, R³ is hydrogen or C₁₋₄ alkyl and Y ishydrogen, C₁₋₄ alkyl or phenyl optionally substituted with one or twohalo atoms; and compounds of formula (I) wherein Z is a radical offormula (a-2) wherein R⁴, R⁵ and R⁶ all being hydrogen, and Y ishydrogen, C₁₋₄ alkyl, cyclopropyl or phenyl optionally substituted withone or two halo atoms; and compounds of formula (I) wherein Z is aradical of formula (a-3) wherein R⁷ is hydrogen, halo or C₁₋₄ alkyloxy,R⁸ is hydrogen, R⁹ is hydrogen, C₁₋₄ alkyl or C₁₋₄ alkyloxy and Y ishydrogen, C₁₋₄ alkyl, cyclopropyl, cyclohexyl, imidazolyl, thienyl orphenyl optionally substituted with one or two substituents eachindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy andtrifluoromethyl; and compounds of formula (I) wherein Z is a radicalhaving the formula (a-4) wherein R¹⁰ and R¹² are hydrogen, R¹¹ is C₁₋₄alkyl and Y is hydrogen.

Preferred compounds of formula (I) wherein Z is a radical of formula(a-1) are those compounds wherein R is hydrogen; --X¹ ═X² -- is aradical of formula (x) or (y); Y is isopropyl, phenyl or halophenyl; R¹and R² are both hydrogen; and R³ is methyl.

Most preferred compounds of formula (I) wherein Z is a radical offormula (a-1) are selected from6-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-2(1H)-quinolinone, thepharmaceutically acid addition salts and possible stereoisomeric formsthereof.

Preferred compounds of formula (I) wherein Z is a radical of formula(a-2) are those compounds wherein R is hydrogen; --X¹ ═X² -- is aradical of formula (x) or (y); Y is cyclopropyl, phenyl or halophenyland R⁴, R⁵ and R⁶ are all hydrogen.

Most preferred compounds of formula (I) wherein Z is a radical offormula (a-2) are selected from6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-3,4-dihydro-2(1H)-quinolinoneand 3,4-dihydro-6-[(1H-imidazol-1-yl)phenylmethyl]-2(1H)-quinolinone,the pharmaceutically acceptable acid addition salts and possiblestereoisomers thereof.

Preferred compounds of formula (I) wherein Z is a radical of formula(a-3) are those compounds wherein R is hydrogen; --X¹ ═X² -- is aradical of formula (x) or (y); Y is phenyl, halophenyl, dihalophenyl,methoxyphenyl or cyclohexyl.

Most preferred compounds of formula (I) wherein Z is a radical offormula (a-3) are selected from6-[(1H-1,2,4-triazol-1-yl)[3-(trifluoromethyl)phenyl]methyl]quinoline,the pharmaceutically acceptable acid addition salts and possiblestereoisomers thereof.

The compounds of formula (I) can be prepared by N-alkylating an azole offormula (II) or an alkali metal salt thereof with a quinoline orquinolinone derivative of formula (III). ##STR4##

In formula (III) W represents an appropriate reactive leaving group suchas, for example, halo, e.g., fluoro, chloro, bromo, iodo or asulfonyloxy group, e.g. 4-methylbenzenesulfonyloxy, benzenesulfonyloxy,2-naphthalenesulfonyloxy, methanesulfonyloxy,trifluoromethanesulfonyloxy and the like reactive leaving groups.

The above described N-alkylation is conveniently carried out by stirringthe reactants in the presence of a suitable solvent such as, forexample, an aromatic hydrocarbon, e.g. benzene, methylbenzene,dimethylbenzene, and the like; an ester, e.g. ethyl acetate,γ-butyrolacetone and the like; a ketone, e.g. 2-propanone,4-methyl-2-pentanone and the like; an ether; e.g. 1,4-dioxane,1,1'-oxybisethane, tetrahydrofuran and the like; a polar aproticsolvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, acetonitrile, hexamethylphosphortriamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, benzonitrile and the like; or a mixtureof such solvents. Somewhat elevated temperatures may be appropriate toenhance the rate of the reaction and in some cases the reaction may evenbe carried out at the reflux temperature of the reaction mixture. Theaddition of an appropriate base such as, for example, an alkali or anearth alkaline metal carbonate, hydrogen carbonate, hydroxide, amide orhydride, e.g. sodium hydroxide, potassium hydroxide, potassiumcarbonate, sodium hydride and the like or an organic base, such as, forexample, N,N-dimethyl-4-pyridinamine, pyridine, N,N-diethylethanamine orN-(1-methylethyl)-2-propanamine may be employed to pick up the acidwhich is liberated during the course of the reaction. In some instancesit may be advantageous to use an excess of the azole (II) or to convertthe azole first into a suitable salt form thereof such as, for example,an alkali or earth alkaline metal salt, by reacting (II) with anappropriate base as defined hereinabove and subsequently using said saltform in the reaction with the alkylating reagent of formula (III).Additionally, it may be advantageous to conduct said N-alkylationreaction under an inert atmosphere such as, for example, oxygen-freeargon or nitrogen gas. Said alkylation may also be carried out byapplying art-known conditions of phase transfer catalysis reactions.

Compounds of formula (I) wherein --X¹ ═X² -- is a bivalent radical offormula (x), said compounds being represented by formula (I-x), may alsobe prepared by reacting a quinoline of formula (III) with a 1-protectedimidazole of formula (II-x) following the N-alkylation proceduresdescribed hereinabove for the preparation of compounds of formula (I)starting from (II) and (III). ##STR5##

In (II-x) P¹ represents a protective group such as, for example, C₁₋₆alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, arylcarbonyl or a tri(C₁₋₆alkyl)silyl group. In some instances the reaction of (II-x) with (III)first yields a 1-protected imidazolium salt of formula (IV) which may insitu, or if desired, after isolating and further purifying it, bedeprotected by stirring it in an aqueous basic or acidic solution.##STR6##

In (IV) W⁻ is an anion arising from an acid such as, for example,hydrochloric acid, hydrobromic acid, methanesulfonic acid,4-methylbenzenesulfonic acid and the like acids.

Compounds of formula (I) wherein --X¹ ═X² -- is a bivalent radical offormula (y), said compounds being represented by formula (I-y), can alsobe prepared by endo-N-alkylation of a triazolamine of formula (II-y)with a quinoline of formula (III) and subsequent deamination of the thusprepared triazolium salt, wherein W⁻ is an anion as defined hereinabove.##STR7##

The endo-N-alkylation reaction of (II-y) with (III) is carried outaccording to similar procedures as described hereinabove for thepreparation of a compound of formula (I) starting from (III) and (II).Said deamination reaction is conveniently conducted by reaction with anacidic nitrite solution in the presence of an appropriate reductant, orby reaction with an alkylnitrite such as, for example,1,1-dimethylethylnitrite or isoamylnitrite and the like. Preferably,said deamination reaction is conducted with an aqueous solution ofnitrous acid or of a nitrite salt in a suitable acid in the presence ofa reducing agent such as, for example, hypophosphorous acid, formicacid, at a lower temperature.

The compounds of formula (I) may also be prepared by reacting anintermediate of formula (V) with a reagent of formula (VI) such as, forexample, a 1,1'-carbonyl-bis[1H-imidazole]. ##STR8##

In (VI) X represents C or S.

Said reaction may conveniently be conducted in a suitable solvent suchas, for example, an ether, e.g. 1,4-dioxane, tetrahydrofuran; ahalogenated hydrocarbon, e.g. di- or trichloromethane; a hydrocarbon,e.g. benzene, methylbenzene, dimethylbenzene; N,N-dimethylformamide,N,N-dimethylacetamide, or a mixture of such solvents. In order toenhance the reaction rate, it may be advantageous to heat the reactionmixture.

The compounds of formula (I) may also be prepared by reacting a ketoneor aldehyde of formula (VII) with an azole (II) in the presence offormic acid or formamides as reducing agents. ##STR9##

Said reductive alkylation can conveniently be conducted by stirring andheating the reagents in formic acid or formamides optionally in thepresence of an acid catalyst. An appropriate acid catalyst for using inthis reaction is for example a mineral acid such as, hydrochloric acid,sulfuric acid or a sulfonic acid such as, methanesulfonic acid,benzenesulfonic acid, 4-methylbenzenesulfonic acid and the like. It maybe appropriate to remove the water which is formed during the reactionby azeotropical distillation, distillation, complexation and the likemethods.

In all of the foregoing and following preparations, the reactionproducts may be isolated from the reaction mixture and, if necessary,further purified according to methodologies generally known in the ansuch as, for example, extraction, distillation, crystallization,trituration and chromatography.

Some compounds of formula (I) can alternatively be prepared undersimilar conditions as are described in the literature for thepreparation of quinolines or quinolinones by cyclizing an intermediateof formula ##STR10##

For example, the compounds of formula (I-a-1) can be prepared bycyclizing an intermediate of formula (IX). ##STR11##

The acid-catalysed cyclization of (IX) can generally be conducted bytreating the intermediate amide (IX) with an appropriate acid such as,for example, sulfuric acid, a hydrohalic acid, e.g. hydrochloric acid,polyphosphoric acid and the like strong acids, optionally at an enhancedtemperature as described for example in J. Med. Chem. 1986, 29,2427-2432.

The compounds of formula (I-a-1), may also be obtained by cyclizing anintermediate of formula (X). ##STR12##

The cyclization reaction of (X) may be conducted according to art-knowncyclizing procedures as described in, for example, Synthesis 1975, 739.Preferably the reaction is carried out in the presence of a suitableLewis Acid, e.g. aluminum chloride either neat or in a suitable solventsuch as, for example, an aromatic hydrocarbon, e.g. benzene,chlorobenzene, methylbenzene and the like; halogenated hydrocarbons,e.g. trichloromethane, tetrachloromethane and the like; an ether, e.g.tetrahydrofuran, 1,4-dioxane and the like or mixtures of such solvents.Somewhat elevated temperatures, preferably between 70°-100° C., andstirring may enhance the rate of the reaction.

Quinolinones of formula (I-a-1) may also be prepared by cyclizing anintermediate of formula (XI). ##STR13##

The cyclization of (XI) can generally be conducted by treating theintermediate propeneamide (XI) with an appropriate acid such as, forexample, sulfuric acid, a hydrohalic acid, e.g. hydrochloric acid,polyphosphoric acid and the like strong acids at room temperature oroptionally at an enhanced temperature as described for example in J.Med. Chem. 1989, 32, 1552-1558 or J. Med. Chem. 1988, 31, 2048-2056.

Alternatively the compounds of formula (I) wherein Z is a radical offormula (a-1) or (a-2) may be prepared by cyclizing an intermediate offormula (XII) or (XIII). ##STR14##

In (XII) and (XIII) R¹³ represents either a hydrogen or a C₁₋₄ alkylgroup. The above mentioned cyclization reactions may carried out bystirring and if desired heating the intermediate starting material,optionally in a suitable reaction-inert solvent. Appropriate solventsfor said cyclization reactions are for example, aromatic hydrocarbons,e.g. benzene, methylbenzene, dimethylbenzene and the like; halogenatedhydrocarbons, e.g. trichloromethane, tetrachloromethane, chlorobenzeneand the like; ethers, e.g. 1,1'-oxybisethane, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and the like, alkanols, e.g. ethanol,propanol, butanol and the like; ketones, e.g. 2-propanone,4-methyl-2-pentanone; dipolar aprotic solvents, e.g.N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, methylacetamide, pyridine and the like, or mixtures of such solvents. Thewater which is liberated during the cyclization reaction may be removedfrom the reaction mixture by azeotropical distillation.

Some compounds of formula (I-a-3), can be prepared by cyclizing anintermediate of formula (XIV). ##STR15##

Said cyclization reaction may conveniently be conducted followingsimilar cyclization procedures as described hereinabove for preparing(I-a-1) from (IX) by cyclizing an intermediate (XIV) in the presence ofa suitable dehydrating agent such as, for example, polyphosphoric acid,phosphorous pentoxide, polyphosphate ester, sulfuric acid and the like.

Alternatively the compounds of formula (I-a-3) can be prepared byreacting an aniline of formula (VIII) with an α,β-unsaturated carbonylsynthon of formula (XV) in the presence of an oxidizing agent. ##STR16##

Said reaction may be conducted by heating the reactants in the presenceof an acid such as, for example, sulfuric acid, a hydrohalic acid, e.g.hydrochloric acid, polyphosphoric acid and the like strong acids and amild oxidizing agent. Appropriate oxidizing agents are for examplearsenic acid, arsenic oxide, boric acid, ferric chloride, silvernitrate, nitrobenzene, 4-nitrobenzenesulfonic acid or a mixture of4-nitrobenzoic acid and 4-aminobenzoic acid and the like.

Compounds of formula (I-a-3) may also be prepared by condensing anortho-acyl aniline of formula (XVI) with a ketone or aldehyde of formula(XVII). ##STR17##

Said cyclization may convenienlty be conducted by mixing the reactantsin a reaction-inert solvent such as, for example, water, an alcohol,e.g. methanol, butanol and the like; an aromatic hydrocarbon, e.g.benzene, methylbenzene, dimethylbenzene and the like, an ester, e.g.,ethyl acetate; a halogenated hydrocarbon, e.g., trichloromethane,dichloromethane and the like; or a mixture of such solvents, preferablyin the presence of a mineral acid such as, for example, hydrochloricacid, sulfuric acid and the like, a carboxylic acid such as, forexample, formic acid, acetic acid and the like, or a sulfonic acid suchas, for example, methanesulfonic acid, benzenesulfonic acid,4-methylbenzenesulfonic acid and the like or in the presence of adehydrating agent, such as polyphosphoric acid, phosphorous pentoxideand the like. Somewhat elevated temperatures may be appropriate toenhance the rate of the reaction and in some cases the reaction may becarried out at the reflux temperature of the reaction mixture. It may beappropriate to remove the water which is liberated during the course ofthe condensation reaction by azeotropical distillation.

The compounds of formula (I) wherein Z is a radical of formula (a-4) andR¹⁰ is hydrogen, said compounds being represented by (I-a-4-a) can beprepared by cyclizing an intermediate of formula (XVIII). ##STR18##

The above mentioned cyclization reaction is preferably accomplished bystirring the intermediate (XVIII) in the presence of a suitabledehydrating agent such as, for example, polyphosphoric acid, phosphorouspentoxide, polyphosphate ester, sulfuric acid and the like, if desiredin a reaction inert solvent.

Alternatively, some compounds of formula (I) may also be preparedaccording to procedures analogous to those described in the literaturefor the preparation of azoles by cyclizing an appropriate startingmaterial.

The compounds of formula (I-x) may also be prepared, for example, bycyclizing an intermediate of formula (XIX) and desulfurating the thusobtained intermediate of formula (XX). ##STR19##

In formulae (XIX) and (XX) R¹⁴ represents hydrogen or C₁₋₆ alkyl and R¹⁵represents C₁₋₆ alkyl or both R¹⁵ taken together form a C₂₋₃ alkanediylradical.

Said cyclization reaction may conveniently be conducted by stirring andheating intermediate (XIX) in an aqueous acidic solvent, e.g. in aqueoushydrochloric or sulfuric acid. The intermediate (XX) may be desulfuratedfollowing art-known procedures, e.g., by treatment with Raney nickel inthe presence of an alkanol, e.g. methanol, ethanol and the like, or bytreatment with nitric acid, optionally in the presence of sodiumnitrite.

The compounds of formula (I-y) may be prepared from a hydrazinederivative of formula (XXI) by reaction with s-triazine following theprocedures described in J. Org. Chem., 1956, 1037. ##STR20##

The intermediate hydrazine (XXI) and the corresponding intermediateamine of formula Y--CH(NH₂)--Z(XXII) may also advantageously beconverted into azoles, wherein --X¹ ═X² -- is a bivalent radical offormula (x), (y) or (z), following the procedures described in U.S. Pat.No. 4,267,179, incorporated herein by reference.

The compounds of formula (I) can also be convened into each otherfollowing art-known functional group transformation procedures.

The compounds of formula (I-a-1) wherein R¹ is hydrogen may be convenedinto compounds of formula (I-a-3) wherein R⁷ is halo by treatment with ahalogenating agent such as, for example, thionyl chloride,pentachlorophosphorane, phosphoryl chloride, sulfuryl chloride and thelike. The thus obtained compounds of formula (I-a-3) wherein R⁷ is halomay further be convened into compounds of formula (I-a-3) wherein R⁷ isC₁₋₆ alkyloxy by reacting the starting compound with an appropriatealcohol, preferably an alkali metal or earth alkaline metal salt of saidalcohol.

Depending on the nature of the substituents the compounds of formula(I-a-1) may also be convened into compounds of formula (I-a-2), by aselective hydrogenation of the starting compound with an appropriatereducing agent such as, for example with a nobel catalyst, such asplatinum-on-charcoal, palladium-on-charcoal and the like.Dehydrogenation of the compounds of formula (I-a-2) may result in acompound of formula (I-a-1). The dehydrogenation may be accomplished bystirring and optionally heating the starting compound with alkalineperoxide, ammoniacal silver nitrate,2,3-dichloro-5,6-dicyano-p-benzoquinone, manganese(IV)oxide, bromine inthe presence of bromobenzene and the like in suitable reaction-inertsolvent. Suitable solvents for said dehydrogenation are, for example,water, alkanols, e.g. methanol, ethanol and the like, ketones, e.g.2-propanone and the like, halogenated hydrocarbons, e.g.trichloromethane, tetrachloromethane and the like, ethers, e.g.1,1-oxybisethane and the like, dipolar aprotic solvents, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and the like, ora mixture of such solvents. Some compounds of formula (I) may also beN-alkylated or N-aminated according to art known procedures.

A number of intermediates and starting materials in the foregoingpreparations are known compounds which may be prepared according toart-known methodologies of preparing said or similar compounds. Someintermediates of the previous reaction schemes are novel and haveespecially been developed for conversion into compounds of the presentinvention.

Intermediates of formula (III), (V) and (VII-a) wherein Y is other thanhydrogen may be prepared from an appropriately substituted quinoline orquinolinone derivative of formula (XXIII) according to the followingreaction sequence. ##STR21##

The hydroxymethyl moiety in the starting intermediate of formula (XXIII)is first converted into a formyl moiety with a suitable oxidant, e.g.manganese(IV) oxide or potassium permanganate, and subsequently reactedwith a metal alkyl, e.g. methyllithium, butyllithium, metal aryl, e.g.phenyllithium, or with a complex metal alkyl or aryl in a suitablesolvent, e.g. tetrahydrofuran, 1,1'-oxybisethane and the like to formthe secundary alcohols (V). The desired intermediates of formula (III)may then be obtained by converting the alcohol function of theintermediate of formula (V) into an appropriate leaving group Wfollowing standard procedures as known in the art. For example, halidesare generally prepared by the reaction of (V) with an appropriatehalogenating agent such as, for example, thionyl chloride, sulfurylchloride, pentachlorophosphorane, pentabromophosphorane,phosphorylchloride, hydrochloric acid, hydrobromic acid and the likehalogenating agents. The intermediates of formula (III) wherein Y ishydrogen can be obtained directly from the intermediates of formula(XXIII) following the procedure described hereinabove for converting (V)into (III).

Some intermediates of formula (III) wherein Y is other than hydrogen mayalso be prepared by acylating a quinoline or quinolinone of formula(XXV) with an appropriate reagent of formula (XXIV) according toan-known Friedel-Crafts acylation reaction procedures, reducing the thusobtained ketone (VII-b) with an appropriate reductant, e.g. sodiumborohydride in a suitable solvent such as water; an alcohol e.g.methanol, ethanol or mixtures thereof with tetrahydrofuran optionally inthe presence of sodium hydroxide and subsequently converting the alcoholfunction into an appropriate leaving group as described hereinbefore.##STR22##

Some intermediates of formula (III) may also be prepared by cyclizing anappropriate benzaldehyde or ketone derivative of the general formula(XXVI) according to similar cyclization procedures as describedhereinabove for the synthesis of the compounds of formula (I-a-1),(I-a-2), (I-a-3) or (I-a-4), reducing the thus obtained quinoline orquinolinone with an appropriate reductant, e.g. sodium borohydride,sodium cyanoborohydride and the like reagents and subsequentlyconverting the alcohol function of (V) in an appropriate leaving group.Depending on the cyclization procedure it may be useful to protect theketone or aldehyde group according to art known procedures e.g. byacetalization. ##STR23##

In (XXVI) the meanings of E¹ and E² are selected in such a manner toenable a cyclization reaction. For example, as appropriate intermediatesof formula (XXVI) there may be mentioned: ##STR24##

Intermediates of formula (IX), (X) and (XI) can conveniently be preparedby reacting an aniline (VIII-a) with respectively a carboxylic acid offormula (XXVII-a), (XXVII-b) or (XXVII-c) or a functional derivativethereof. ##STR25##

Said functional derivatives of formula (XXVII-a), (XXVII-b) and(XXVII-c) are meant to comprise the halide, anhydride, amide and esterforms of (XXVII-a), (XXVII-b) and (XXVII-c). (XXVII-a) may also be inthe form of a reactive lactone such as, for example,4-methylene-2-oxetanone.

Functional derivatives may be prepared following art-known procedures,for example, by reacting the carboxylic acid of formula (XXVII) withthionyl chloride, phosphorous trichloride, polyphosphoric acid,phosphoryl chloride and the like, or by reacting the carboxylic acid offormula (XXVII) with an acyl halide, e.g. acetyl chloride, ethylcarbonochloridate and the like. Or the intermediates (VIII-a) and(XXVII) may be coupled in the presence of a suitable reagent capable offorming amides, e.g. 1,1'-carbonylbis[1H-imidazole],dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide and thelike.

Said amidation reactions may conveniently be carried out by stirring thereactants in a suitable reaction-inert solvent, such as, for example, ahalogenated hydrocarbon, e.g. dichloromethane, trichloromethane and thelike, an aromatic hydrocarbon, e.g. methylbenzene and the like, anether, e.g. 1,1'-oxybisethane, tetrahydrofuran and the like or a dipolaraprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide andthe like. The addition of a suitable base may be appropriate inparticular a tertiary amine such as, N,N-diethylethanamine. The water,the alcohol or the acid which is liberated during the course of thereaction may be removed from the reaction mixture accordingmethodologies generally known in the art such as, for example,azeotropical distillation, complexation and salt formation.

When a reactive lactone of formula (XXVII-a) is used the reaction may becarried out according to similar procedures as outlined in OrganicSynthesis, Willy New York, 1955, Collect. Vol. III page 10.

The intermediate of formula (XII) and/or (XIII) can be prepared byreducing the nitro derivative of formula (XXVIII) in the presence ofhydrogen and a suitable metal catalyst such as, for example,palladium-on-charcoal, platinum oxide and the like catalysts. The nitroderivative of formula (XXVIII) in turn can be prepared from an aldehydeof formula (XXIX) by reacting the latter with a phosphorous ylide offormula (XXX) or with an ylide of formula (XXXI) prepared from aphosphonate. ##STR26##

In formula (XXVIII) R¹³ represents hydrogen or C₁₋₄ alkyl. The reactionof (XXIX) with (XXX) or (XXXI) can conveniently be conducted by treatinga phosphonium salt or a phosphonate with an appropriate base such as,for example, butyllithium, methyllithium, sodium amide, sodium hydride,a sodium or potassium alkoxide, sulfinylbis(methane) sodium salt and thelike bases, under an inert atmosphere and in a reaction-inert solventsuch as for example, a hydrocarbon, e.g. hexane, heptane, cyclohexaneand the like; an ether, e.g. 1,1'-oxybisethane, tetrahydrofuran,1,2-dimethoxyethane and the like; a dipolar aprotic solvent, e.g.dimethylsulfoxide, hexamethylphosphor triamide, and the like solvents.

The starting intermediate (XXIX) wherein the 1H-azole-1-ylmethyl moietyis substituted in the para position can for example be preparedaccording the following reaction sequence. ##STR27##

In formula (XXXII) W¹ represents a reactive leaving group such as, forexample, halo, e.g. chloro or fluoro, nitro, 4-methylbenzenesulfonyloxy,phenyloxy, alkyloxy and the like groups.

a) The aromatic nucleophilic substitution on a nitrobenzene of formula(XXXII) with a cyanide of formula (XXXIII) can be conducted by stirringthe reactants in the presence of a base in a reaction inert solvent suchas for example, a dipolar aprotic solvent, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, pyridine,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethylimidazolidinone, 1,1,3,3-tetramethylurea,1-methyl-2-pyrrolidinone, nitrobenzene and the like solvents; ormixtures thereof. Appropriate bases are sodium hydride, sodium amide,sulfinylbis(methane) sodium salt and the like bases. It may beadvantageous to add to the reaction mixture a crown ether, e.g.1,4,7,10,13,16-hexaoxacyclooctadecane and the like or a complexing agentsuch as for example, tris[2-(2-methoxyethoxy)]ethanamine and the like.Somewhat elevated temperatures may enhance the rate of the reaction.

b) The oxidation of the cyanide of formula (XXXIV) can be accomplishedfollowing art-known oxidation procedures as described in J. Org. Chem.,1975, 40, 267.

c) The reduction of the aldehyde or ketone of formula (XXXV) can becarried out by stirring the latter with an appropriate reductant, e.g.sodium borohydride in a suitable solvent, e.g. methanol, ethanol.

d) The halogenation of the alcohol of formula (XXXVI) can beaccomplished by reacting the alcohol with a suitable halogenating agent,e.g., thionyl chloride, methanesulfonyl chloride and the like.

e) The introduction of the azole can be carried out according proceduresoutlined hereinbefore for the synthesis of (I) from (II) and (III).

f) The deprotection of the carboxaldehyde group of (XXXVIII) can easilybe conducted following art-known methods of hydrolyzing acetals, e.g. byacid hydrolysis in an aqueous medium.

The intermediates of formula (XIV) and (XVIII) may be prepared byreacting an aniline of formula (VIII) with a 1,3-dicarbonyl of formulaR⁷ --C(═O)--CHR⁸ --C(═O)--R⁹ (IXL) or R¹¹ --C(═O)--CHR¹²--C(═O)--O--C₁₋₄ alkyl (XL) in a reaction-inert solvent in the presenceof an appropriate acid catalyst such as, for example, a sulfonic acid,e.g. methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid and the like acids.

The starting compounds of formula (VIII) can easily be preparedaccording to procedures described in U.S. Pat. No. 4,859,684corresponding to EP-A-260,744 incorporated herein by reference for theprocess of preparing the intermediate of formula (VIII).

The intermediate hydrazines (XXI) and amines (XXII) may conveniently beprepared from a ketone of formula (VII) by reaction with either an acidaddition salt thereof, or with hydroxylamine or hydrazine or an acidaddition salt or a solvate thereof, and reducing the thus obtained oximeor hydrazone, for example, by catalytic hydrogenation in the presence ofhydrogen and an appropriate hydrogenation catalyst, e.g. Raney nickeland the like.

The intermediates of formula (XIX) can be prepared from an amine offormula (XXII) by reaction with a reagent of formula (XLI) andoptionally S-alkylating the thus obtained thiourea with a C₁₋₆alkylhalide. ##STR28##

The compounds of formula (I) and some of the intermediates in thisinvention have an asymmetric carbon atom in their structure. This chiralcenter may be present in a R- and a S-configuration, this R- andS-notation being in correspondence with the rules described in PureAppl. Chem., 1976, 45, 11-30.

Pure stereochemically isomeric forms of the compounds of this inventionmay be obtained by the application of art-known procedures.Diastereoisomers may be separated by physical separation methods such asselective crystallization and chromatographic techniques, e.g. countercurrent distribution, and enantiomers may be separated from each otherby the selective crystallization of their diastereomeric salts withoptically active acids.

Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically.

The compounds of the present invention, their pharmaceuticallyacceptable acid addition salts and their possible stereochemicallyisomeric forms have useful pharmacological properties. For example, theysuppress the plasma elimination of retinoids, such as,all-trans-retinoic acid, 13-cis retinoic acid and their derivatives. Thelatter results in more sustained/higher tissue concentrations ofretinoic acid and improved control of the differentiation and growth ofvarious cell types. In addition some compounds inhibit the formation ofandrogens from progestines and/or inhibit the action of the enzymecomplex aromatase which catalyses the formation of estrogens fromandrogenic steroids in mammals. A number of compounds also show aninhibitory action on the biosynthesis of thromboxane A₂.

Said property of the compounds of the invention to delay the metabolismof retinoic acid can easily be evidenced in various in vivo experiments.A particular test procedure is described hereinafter as the "Metabolismof endogenous or exogenously administered all-trans-retinoic acid" testand demonstrates the suppression of the plasma elimination of endogenousor exogenously administered all-trans-retinoic acid. As such, thecompounds of formula (I) can be used to control the rate of growth anddifferentiation of various cell types which effects are known to beaffected by retinoids. The ability of retinoids, such as,13-cis-retinoic acid, all-trans-retinoic acid and their derivatives tomodulate differentiation and proliferation in several cell types whetherthey are of epithelial or mesenchymal origin is extensively studied andreviewed in J. Clin. Chem. Clin, Biochem., 26, 479-488 (1983);Pharmacological Reviews 36, 935-1005, (1984), Arch. Dermatol. 117,160-180; (1981) and Journal of Medicinal Chemistry 25, 1269-1277,(1982).

In view of their capability to delay the metabolism of retinoic acid thecompounds can thus be used in the treatment of disorders which arecharacterized by an increased proliferation and/or abnormaldifferentiation of epithelial cells. In particular the compounds of theinvention can be used for treatment of carcinoma which is essentially aderailment of cellular differentiation, occurring in epithelial tissues.Other uses include, in addition to cancer treatment, the treatment of avariety of disorders of keratinization such as, for example, acne,psoriasis, lamellar ichthyosis, plantar warts, callosities, acanthosisnigricans, lichen planus, molluscum, melasma, corneal epithelialabrasion, geographic tongue, Fox-Fordyce disease, cutaneous metastaticmelanoma and keloids, epidermolytic hyperkeratosis, Darier's disease,pityriasis rubra pilaris, congenital ichthyosiform erythroderma,hyperkeratosis palmaris et plantaris, and similar diseases.

The anti-tumor activity may be demonstrated in several retinoicacid-sensitive and insensitive cell lines and solid tumors such as, forexample, in Ta3-Ha induced mamma tumors in female mice.

The inhibition of androgen and/or estrogen formation can be demonstratedby analyzing the effects of the compounds of the invention on theconversion of progestins into androgens in the presence of testicularmicrosomes or on the conversion of androstenedione into estrone andestradiol in the presence of human placental microsomes. The invivo-inhibition of androgen or estrogen formation can, for example, bedemonstrated by measuring the suppression of the plasma testosterone orestrogen concentration in dogs, rats or mice. A number of relevant testshave been described in EP-A-260,744 and EP-A-293,978, both incorporatedherein by reference. In view of their capability to inhibit thebiosynthesis of estrogens and/or androgens the compounds can be used inthe treatment of estrogen or androgen dependent disorders such as, forexample, breast cancer, endometriosis, endometrial cancer, polycysticovarian disease, benign breast disease, prostatic cancer and hirsutism.

The beneficial effect of androgen inhibitors in these disorders,especially in the treatment of prostatic cancer, is described in, e.g.,Journal of Urology 132, 61-63 (1984). The beneficial effect of aromataseinhibitors in these disorders, especially in the treatment of breastcancer, is described in, e.g. Cancer Research, 42, Suppl. 8: 3261s(1982).

In view of the usefulness of the subject compounds it is evident thatthe present invention provides a method for treating mammals sufferingfrom disorders which are characterized by an increased proliferationand/or abnormal differentiation of normal, preneoplastic or neoplasticcells, whether they are epithelial or mesenchymal; whether they are ofectodermal, endodermal or mesodermal origin; or whether they areestrogen dependent, androgen dependent or nonestrogen and nonandrogendependent. Said method comprises the systemic or topical administrationto the latter of an amount, effective to treat said disorders, of acompound of formula (I), a pharmaceutically acceptable acid-additionsalt, or a possible stereochemically isomeric form thereof. Inparticular the present invention provides a method in which the growthand differentiation in said normal, preneoplastic and neoplastic cellsis sensitive to the actions of retinoids.

Those of skill in treating disorders which are characterized by anexcessive proliferation and/or abnormal differentiation of tissues coulddetermine the effective amount from the test results presentedhereinafter. In general it is contemplated than an effective amountwould be from 0.001 mg/kg to 50 mg/kg body weight and more preferablyfrom 0.01 mg/kg to 10 mg/kg body weight.

The subject compounds may be formulated into various pharmaceuticalforms for administration purposes. As appropriate compositions there maybe cited all compositions usually employed for systemically or topicallyadministering drugs. To prepare the pharmaceutical compositions of thisinvention, an effective amount of the particular compound, optionally inacid-addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable,particularly, for administration orally, rectally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid careers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represents the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid careers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be convened, shortly before use, to liquid form preparations. In thecompositons suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin.

As appropriate compositions for topical application there may be citedall compositions usually employed for topically administering drugs,e.g., creams, gellies, dressings, shampoos, tinctures, pastes,ointments, salves, powders and the like. Application of saidcompositions may be by aerosol e.g. with a propellent such as nitrogencarbon dioxide, a freon, or without a propellent such as a pump spray,drops, lotions, or a semisolid such as a thickened composition which canbe applied by a swab. In particular compositions, semisolid compositionssuch as salves, creams, gellies, ointments and the like willconveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powders packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Other such compositions are preparations of the cosmetic type, such astoilet waters, packs, lotions, skin milks or milky lotions. Saidpreparations contain, besides the active ingredient, components usuallyemployed in such preparations. Examples of such components are oils,fats, waxes, surfactants, humectants, thickening agents, antioxidants,viscosity stabilizers, chelating agents, buffers, preservatives,perfumes, dyestuffs, lower alkanols, and the like. If desired, furtheringredients may be incorporated in the compositions, e.g.antiinflammatory agents, antibacterials, antifungals, disinfectants,vitamins, sunscreens, antibiotics, or other agents.

Examples of oils comprise fats and oils such as olive oil andhydrogenated oils; waxes such as beeswax and lanolin; hydrocarbons suchas liquid paraffin, ceresin, and squalane; fatty acids such as stearicacid and oleic acid; alcohols such as cetyl alcohol, stearyl alcohol,lanolin alcohol, and hexadecanol; and esters such as isopropylmyristate, isopropyl palmitate and butyl stearate. As examples ofsurfactants there may be cited anionic surfactants such as sodiumstearate, sodium cetylsulfate, polyoxyethylene lauryl-ether phosphate,sodium N-acyl glutamate; cationic surfactants such asstearyl-dimethyl-benzylammonium chloride and stearyltrimethylammoniumchloride; ampholytic surfac-tants such as alkylaminoethylglycinehydrochloride solutions and lecithin; and nonionic surfactants such asglycerin monostearate, sorbitan monostearate, sucrose fatty acid esters,propylene glycol monostearate, polyoxyethylene oleylether, polyethyleneglycol monostearate, polyoxyethylene sorbitan monopalmitate,polyoxyethylene coconut fatty acid monoethanolamide, polyoxyethylenepolyoxypropylene glycol (e.g. the materials sold under the trademark"Pluronic"), polyoxyethylene castor oil, and polyoxyethylene lanolin.Examples of humectants include glycerin, 1,3-butylene glycol, andpropylene glycol; examples of lower alcohols include ethanol andisopropanol; examples of thickening agents include xanthan gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethyleneglycol and sodium carboxymethyl cellulose; examples of antioxidantscomprise butylated hydroxytoluene, butylated hydroxyanisole, propylgallate, citric acid and ethoxyquin; examples of chelating agentsinclude disodium edetate and ethanehydroxy diphosphate; examples ofbuffers comprise citric acid, sodium citrate, boric acid, borax, anddisodium hydrogen phosphate; and examples of preservatives are methylparahydroxybenzoate, ethyl parahydroxybenzoate, dehydroacetic acid,salicylic acid and benzoic acid. For preparing ointments, creams, toiletwaters, skin milks, and the like, typically from 0.01 to 10% inparticular from 0.1 to 5% and more in particular from 0.2 to 2.5% of theactive ingredient will be incorporated in said compositions. Inointments or creams, the carrier for example consists of 1 to 20%, inparticular 5 to 15% of a humectant, 0.1 to 10% in particular from 0.5 to5% of a thickener and water, or said carrier may consist of 70 to 99%,in particular 20 to 95% of a surfactant, and 0 to 20%, in particular 2.5to 15% of a fat; or 80 to 99.9% in particular 90 to 99% of a thickener;or 5 to 15% of a surfactant, 2-15% of a humectant, 0 to 80% of an oil,very small (<2%) amounts of preservative, colouring agent and/orperfume, and water. In a toilet water, the carrier for example consistsof 2 to 10% of a lower alcohol, 0.1 to 10% or in particular 0.5 to 1% ofa surfactant, 1 to 20%, in particular 3 to 7% of a humectant, 0 to 5% ofa buffer, water and small amounts (<2%) of preservative, dyestuff and/orperfume. In a skin milk, the carrier typically consists of 10-50% ofoil, 1 to 10% of surfactant, 50-80% of water and 0 to 3% of preservativeand/or perfume. In the afore-mentioned preparations, all % symbols referto weight by weight percentage. The humectant, surfactant, oil, etc . .. referred to in said preparations may be any such component used in thecosmetic arts but preferably will be one or more of the componentsmentioned hereinabove. Further, when in the above compositions one ormore of the components make up the major part of the composition, theother ingredients can evidently be not present at their indicatedmaximum concentration and therefore will make up the remainder of thecomposition.

Particular compositions for use in the method of the present inventionare those wherein the active ingredient is formulated inliposome-containing compositions. Liposomes are artificial vesiclesformed by amphiphatic molecules such as polar lipids, for example,phosphatidyl cholines, ethanolamines and serines, sphingomyelins,cardiolipins, plasmalogens, phosphatidic acids and cerebiosides.Liposomes are formed when suitable amphiphathic molecules are allowed toswell in water or aqueous solutions to form liquid crystals usually ofmultilayer structure comprised of many bilayers separated from eachother by aqueous material (also referred to as coarse liposomes).Another type of liposome known to be consisting of a single bilayerencapsulating aqueous material is referred to as a unilamellar vesicle.If water-soluble materials are included in the aqueous phase during theswelling of the lipids they become entrapped in the aqueous layerbetween the lipid bilayers.

In a further aspect of the invention there are provided particularpharmaceutical or cosmetical compositions which comprise an inertcarrier, an effective amount of a compound of formula (I) an acidaddition salt or a stereochemically isomeric form thereof and aneffective amount of a retinoic acid, a derivative thereof or astereochemically isomeric form thereof. Said retinoic acid containingcompositions are particularly useful for treating acne or for retardingthe effects of aging of the skin and generally improve the quality ofthe skin, particularly human facial skin. A pharmaceutical or cosmeticalcomposition containing retinoic acid or a derivative thereof as theactive ingredient in intimate admixture with a dermatologicallyacceptable career can be prepared according to conventional compoundingtechniques, such as those known for topical application of retinoic acidand its derivatives. Conventional pharmaceutical compounding techniquesfor topical application of retinoic acid are described for example in,U.S. Pat. Nos. 3,906,108 and 4,247,547, which are incorporated herein byreference. Preferred composition for topical application are in form ofa cream, ointment or lotion comprising from 0.005 to 0.5% (particularlyfrom 0.01 to 0.1%) all-trans-retinoic acid, 13-cis-retinoic acid or aderivative thereof and from 0.1 to 5% of a compound of formula (I) and,a dermatologically acceptable acid addition salt thereof or astereochemically isomeric form thereof, in a semi-solid or liquiddiluent or carrier. These preferred compositions should preferably benon-irritating and as far as possible they should be odorless andnon-toxic. For convenience in applying to the skin, the compositionusually contain, besides water or an organic solvent, several of certainorganic emollients, emulsifiers for the aqueous and/or non aqueousphases of the compositions, wetting agents preservatives and agents thatfacilitate the penetration and remainence of the active agents in theskin.

The following examples are intended to illustrate and not to limit thescope of the present invention. Unless otherwise stated all partstherein are by weight.

EXPERIMENTAL PART A. Preparation of the Intermediates Example 1

a) A mixture of 8.6 parts of 7-quinolinemethanol, 20 parts ofmanganese(IV)oxide and 130 parts of dichloromethane was stirred for 24hours at room temperature. The reaction mixture was filtered overdiatomaceous earth and the filtrate was evaporated. The residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 98:2).The eluent of the desired fraction was evaporated, yielding 8 parts(94.2%) of 7-quinolinecarboxaldehyde; mp. 56° C. (interm. 1).

b) To a stirred mixture of 1.25 parts of magnesium, 14 parts of1,1'-oxybisethane and 8 parts of bromobenzene was added a solution of 8parts of intermediate 1, namely 7-quinolinecarboxaldehyde, in 72 partsof tetrahydrofuran, keeping the temperature between 0° C. and 5° C.After stirring for 12 hours at room temperature, the reaction mixturewas poured into 300 parts of ice-water. The product was extracted with1,1'-oxybisethane (3×70 parts). The combined extracts were dried,filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH 98:2). The eluent of thedesired fraction was evaporated, yielding 3.2 parts (26.6%) ofα-phenyl-7-quinolinemethanol; mp. 118° C. (interm. 2).

In a similar manner there were also prepared the intermediates listed inTable 1.

                  TABLE 1                                                         ______________________________________                                         ##STR29##                                                                    Int. No. R            physical data (mp. in °C.)                       ______________________________________                                        3        C.sub.6 H.sub.5                                                                            98                                                      4        3-ClC.sub.6 H.sub.4                                                                        112                                                     5        3-FC.sub.6 H.sub.4                                                                         94                                                      6        4-ClC.sub.6 H.sub.4                                                                        148                                                     7        3-CH.sub.3 C.sub.6 H.sub.4                                                                 122                                                     8        3-CH.sub.3 OC.sub.6 H.sub.4                                                                142                                                     9        3,4-di(F)C.sub.6 H.sub.3                                                                   --                                                      10       3,4-di(CH.sub.3)C.sub.6 H.sub.3                                                            114                                                     11       3-CF.sub.3 C.sub.6 H.sub.4                                                                 --                                                      12       4-FC.sub.6 H.sub.4                                                                         128                                                     13       4-CH.sub.3 OC.sub.6 H.sub.4                                                                164                                                     14       4-CH.sub.3 C.sub.6 H.sub.4                                                                 135                                                     15       c.C.sub.6 H.sub.11                                                                         118                                                     ______________________________________                                    

Example 2

a) A mixture of 34 parts of 6-quinolinemethanol, 70 parts ofmanganese(IV)oxide and 300 parts of trichloromethane was stirred for 24hours at room temperature. The reaction mixture was filtered overdiatomaceous earth and the filtrate was evaporated, yielding 27.7 parts(82.7%) of 6-quinolinecarboxaldehyde; mp. 72° C. (interm. 16).

b) To a stirred and cooled (-5°/0° C.) solution of 5.4 parts ofthiophene in 21.3 parts of 1,1'-oxybisethane were added portionwise 43.5parts of a solution of n. butyllithium in hexanes 1.6M. After stirringfor 20 min. at 0° C., there was added a solution of 5 parts ofintermediate 16, namely 6-quinolinecarboxaldehyde, in 71.2 parts oftetrahydrofuran. Stirring at 0° C. was continued for 1 hour and then thereaction mixture was poured into 200 parts of ice-water. The product wasextracted with 1,1'-oxybisethane and the extract was dried, filtered andevaporated. The residue was purified by column chromatography (silicagel; CH₂ Cl₂ /CH₃ OH 95:5). The eluent of the desired fraction wasevaporated, yielding 2.4 parts (31.1%) ofα-(2-thienyl)-6-quinolinemethanol (interm. 17).

Example 3

a) To a stirred amount of 45.3 parts of aluminiumtrichloride were addeddrop wise 6.9 parts of N,N-dimethylformamide. After stirring for 5 min.at 70° C., there were added portionwise 5 parts of3,4-dihydroquinolin-2(1H)-one and, after another 5 min., 4.7 parts ofbenzoylchloride. Stirring at 70° C. was continued for 2 hours and thenthe reaction mixture was carefully poured into ice-water. There wereadded 50 ml of HCl 12N and the whole was stirred for 15 min. Theprecipitate was filtered off and boiled in 2-propanol. The product wasfiltered off, washed with 2-propanol and 2,2'-oxybispropane and dried invacuo at 60° C., yielding 6.3 parts (73.8%) of6-benzoyl-3,4-dihydro-2(1H)-quinolinone; mp. 211.0° C. (interm. 18).

b) To a suspension of 27.3 parts of intermediate 18, namely6-benzoyl-3,4-dihydro-2(1H)-quinolinone, in 790 parts of methanol wereadded 115 parts of an aqueous sodium hydroxide solution 1N. Afterstirring for 10 min., there were added at once 4.54 parts of sodiumtetrahydroborate. Stirring was continued over weekend at roomtemperature. Them were added 110 ml of HCl 1N and 1000 parts of water.The precipitate was faltered off, stirred in water for 15 min and thentaken up in a mixture of methanol and methylbenzene. This solution wasevaporated and the residue was co-evaporated with methylbenzene. Theproduct was filtered off and dried at 70° C., yielding 21.9 parts(78.6%) of 3,4-dihydro-6-(hydroxyphenylmethyl)-2(1H)-quinolinone; mp.175.0° C. (interm. 19).

In a similar manner there were also prepared:

6-[(3-chlorophenyl)hydroxymethyl]-3,4-dihydro-2(1H)-quinolinone; mp.181.1° C. (interm. 20);

3,4-dihydro-6-(1-hydroxyethyl)-2(1H)-quinolinone; mp. 174.5° C. (interm.21); and

3,4-dihydro-6-[hydroxy(isopropyl)methyl]-2(1I-I)-quinolinone; mp. 194.4°C. (interm. 22).

Example 4

A mixture of 3.2 parts of intermediate 2, namelyα-phenyl-7-quinolinemethanol, 8 parts of thionyl chloride and 65 partsof dichloromethane was stirred for 4 hours at room temperature. Thereaction mixture was evaporated and the residue was poured into water.The product was extracted with dichloromethane (3×39 parts) and thecombined extracts were dried, filtered and evaporated, yielding 3.4parts (98.5%) of 7-(chlorophenylmethyl)quinoline (interm. 23).

In a similar manner there were also prepared the intermediates listed inTable 2.

                  TABLE 2                                                         ______________________________________                                         ##STR30##                                                                    Int. No.            R                                                         ______________________________________                                        24                  3-Cl                                                      25                  H                                                         26                  3-F                                                       27                  4-Cl                                                      28                  3-CH.sub.3                                                29                  3-CH.sub.3 O                                              30                  3,4-di(F)                                                 31                  3,4-di(CH.sub.3                                           32                  3-CF.sub.3                                                33                  4-CH.sub.3                                                34                  4-F                                                       35                  4-CH.sub.3 O                                              ______________________________________                                    

Example 5

To a stirred mixture of 2 parts of intermediate 21, namely3,4-dihydro-6-(1-hydroxyethyl)-2(1H)-quinolinone in 8.9 parts oftetrahydrofuran were added 1.62 parts of thionyl chloride. Stirring atroom temperature was continued overnight. The reaction mixture wasevaporated and the residue was co-evaporated with methylbenzene,yielding 2.3 parts (93.4%) of6-(1-chloroethyl)-3,4-dihydro-2(1H)-quinolinone hydrochloride (interm.36).

Example 6

A mixture of 20 parts of intermediate 19, namely3,4-dihydro-6-(hydroxyphenylmethyl)-2(1H)-quinolinone and 355 parts of asolution of hydrobromic acid in acetic acid 30% was stirred overnight atroom temperature. The reaction mixture was evaporated and the residuewas stirred in ethyl acetate. The product was filtered off, washed withethyl acetate and 2,2'-oxybispropane and dried in vacuo at 35° C.,yielding 23 parts (67.2%) of6-[bromophenylmethyl]-3,4-dihydro-2(1H)-quinolinone hydrobromidedihydrate; mp. 119.5° C. (interm. 37).

In a similar manner there were also prepared:

6-[bromo(3-chlorophenyl)methyl]-3,4-dihydro-2(1H)-quinolinonehydrobromide (interm. 38); and

6-[bromocyclohexylmethyl]quinoline (interm. 39).

Example 7

a) To a stirred and cooled (0° C.) amount of 55.2 parts of sulfuric acidwere added portionwise 13 parts of1-(2-methyl-1-phenylpropyl)-1H-imidazole mononitrate. After stirring for1/2 hour at 0° C., the reaction mixture was poured into ice-water. Thewhole was basified with ammonia and extracted with dichloromethane. Theextract was dried, filtered and evaporated, yielding 12 parts (97.8%) of1-[2-methyl-1-(4-nitrophenyl)propyl]-1H-imidazole (interm. 40).

b) A mixture of 12 parts of intermediate 40, namely1-[2-methyl-1-(4-nitrophenyl)propyl]-1H-imidazole, and 79 parts ofmethanol was hydrogenated for 1 hour at room temperature and 2.10⁵ Pawith 3 parts of Raney nickel. The catalyst was filtered off and thefiltrate was evaporated, yielding 12 parts (100%) of4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (interm. 41).

Example 8

a) To a stirred solution of 88.7 parts of1-[chlorophenylmethyl]-4-nitrobenzene in 790 parts of acetonitrile wereadded 121.8 parts of 1H-imidazole. After stirring for 24 hours at refluxtemperature, the reaction mixture was evaporated. The residue was takenup in methylbenzene. This solution was washed with K₂ CO₃ (aq.), dried,filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH 98:2). The eluent of thedesired fraction was evaporated, yielding 53 parts (53%) of1-[(4-nitrophenyl)phenylmethyl]-1H-imidazole (interm. 42).

b) A solution of 39 parts of intermediate 42, namely1-[(4-nitrophenyl)phenylmethyl]-1H-imidazole, in 240 parts of ethanolwas hydrogenated at 3.10⁵ Pa and at room temperature with 20 parts ofRaney nickel. After the calculated amount of hydrogen was taken up, thecatalyst was filtered off and the filtrate was evaporated, yielding 34.6parts (99.1%) of 4-[(1H-imidazol-1-yl)phenylmethyl]-benzenamine (interm.43).

In a similar manner there were also prepared:

4-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]benzenamine (interm. 44);and

4-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]benzenamine (interm. 45).

Example 9

a) To a stirred and cooled (0° C.) mixture of 5 parts ofN-[4-[(3-chlorophenyl)hydroxymethyl]phenyl]acetamide, 66.5 parts ofdichloromethane and 5.5 parts of N,N-diethylethanamine was added asolution of 3.1 parts of methanesulfonyl chloride in 13.3 parts ofdichloromethane under a nitrogen atmosphere. After stirring for 1 hour,the reaction mixture was evaporated, yielding 8 parts (100%) of4-(acetylamino)-α-(3-chlorophenyl)benzenemethanolmethanesulfonate(ester) (interm. 46).

b) A mixture of 8 parts of intermediate 46, namely4-(acetylamino)-α-(3-chlorophenyl) benzenemethanolmethanesulfonate(ester), 10 parts of 1H-imidazole and 39.5 parts ofacetonitrile was stirred for 2 hours at reflux temperature. The reactionmixture was evaporated and the residue was extracted with ethyl acetate.The extract was washed with NaHCO₃ (aq.), dried, filtered andevaporated, yielding 18 parts (100%) ofN-[4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]phenyl]acetamide (interm.47).

c) A mixture of 80 parts of intermediate 47, namelyN-[4-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]phenyl]acetamide, 150 mlof an aqueous hydrochloric acid solution 2N and 15.8 parts of methanolwas stirred for 2 hours at reflux temperature. The reaction mixture wasevaporated and the residue was basified. The product was extracted withdichloromethane and the extract was dried, filtered and evaporated. Theresidue was purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃OH 98:2). The eluent of the desired fraction was evaporated, yielding14.1 parts (20.2%) of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]benzenamine (interm. 48).

In a similar manner there was also prepared:

4-[(3-fluorophenyl)(1H-imidazol-1-yl)methyl]benzenamine (interm. 49).

Example 10

To a stirred and cooled (0° C.) mixture of 14.6 parts of4-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]benzenamine. 60.9 parts ofbenzene and 6.86 parts of pyridine was added a solution of 10.6 parts of3-phenyl-2-propenoyl chloride in 17.4 parts of benzene under a nitrogenatmosphere. After stirring overnight at room temperature, the reactionmixture was basified and extracted with ethyl acetate. The extract waswashed with water, dried, filtered and evaporated. The residue wascrystallized from dichloromethane. The product was filtered off anddried, yielding 17.7 parts (83.8%) of N-[4-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]phenyl]-3-phenyl-2-propenamide; mp. 244° C.(interm. 50).

In a similar manner there were also prepared the intermediates listed inTable 3:

                  TABLE 3                                                         ______________________________________                                         ##STR31##                                                                    Int. No.   R        physical data (mp. in °C.)                         ______________________________________                                        51         C.sub.6 H.sub.5                                                                        --                                                        52         i.C.sub.3 H.sub.7                                                                      217                                                       53         3-ClC.sub.6 H.sub.4                                                                    --                                                        54         3-FC.sub.6 H.sub.4                                                                     --                                                        55         4-FC.sub.6 H.sub.4                                                                     --                                                        56         H        195                                                       ______________________________________                                    

Example 11

To a stirred solution of 10 parts of4-[(1H-imidazol-1-yl)methyl]benzenamine in 180 parts of1,2-dichloroethane were added dropwise 3.9 parts of4-methylene-2-oxetanone. After stirring for 1/2 hour at roomtemperature, the precipitate was filtered off, washed with1,2-dichloroethane and dried, yielding 9.8 parts (74.8%) ofN-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-oxobutanamide; mp. 175° C.(interm. 57).

In a similar manner there were also prepared the intermediates listed inTable 4:

                  TABLE 4                                                         ______________________________________                                         ##STR32##                                                                    Int. No.    R      physical data (mp. in °C.)                          ______________________________________                                        58          H      --                                                         59          4-F    --                                                         60          4-Cl   --                                                         61          3-Cl   --                                                         62          3-F    --                                                         ______________________________________                                    

B. Preparation of the Final Compounds Example 12

A mixture of 3.4 parts of 7-[chlorophenylmethyl]quinoline, 4.5 parts of1H-imidazole and 72 parts of N,N-dimethylformamide was stirred for 6hours at 80° C. The reaction mixture was evaporated to dry and theresidue was taken up in water. The product was extracted three timeswith 65 parts of dichloromethane. The combined extracts were dried,filtered and evaporated. The residue was purified by columnchromatograhpy over silica gel using a mixture of dichloromethane andmethanol (95:5 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was crystallized from amixture of 2,2'-oxybispropane and 2-propanone. The product was filteredoff and dried, yielding 1.27 parts (33.2%) of 7-[(1H-imidazol-1-yl)phenylmethyl]quinoline; mp. 110.7° C. (compound 36).

Example 13

A mixture of 12.3 parts of 6-(chloromethyl)quinoline, 9.5 parts of1H-imidazole, 19.2 parts of potassium carbonate and 135 parts ofN,N-dimethylformamide was stirred for 3 hours at 80° C. Afterevaporation to dry, the residue was taken up in water and furtherpurified according to similar procedures as described in example 12,yielding 10 parts (48%) of 6-(1H-imidazol-1-ylmethyl)quinolinedihydrochloride; mp. 254.6° C. (compound 29).

Example 14

A mixture of 5.34 parts of 6-[chloro(4-chlorophenyl)methyl]quinoline,6.4 parts of 1H-1,2,4-triazole, 1.26 parts of potassium carbonate and 79parts of acetonitrile was stirred for 8 hours at reflux temperature.After evaporation to dry, the residue was taken up in water and wasfurther purified according to similar procedures as described in example12, yielding 3 parts (49.2%) of6-[(4-chlorophenyl)(4H-1,2,4-triazol-4-yl)methyl]quinoline hemihydrate;mp. 87.8° C. (compound 65).

Example 15

A mixture of 2.3 parts of6-(1-chloroethyl)-3,4-dihydro-2(1H)-quinolinone hydrochloride, 24 partsof acetonitrile, 7.7 parts of dimethyl sulfoxide and 3.8 parts of1H-imidazole was stirred overnight at 60°-70° C. The reaction mixturewas poured into water, extracted and further purified according similarprocedures as described in example 12, yielding 1.2 parts (53.5%) of3,4-dihydro-6-[1-(1H-imidazol-1-yl)ethyl]-2(1H)-quinolinone; mp. 184.8°C. (compound 21).

Example 16

A mixture of 15 parts of α-phenyl-6-quinolinemethanol, 21 parts of1,1'-carbonylbis[1H-imidazole] and 135 parts of N,N-dimethylformamidewas stirred for 12 hours at room temperature. After evaporation to dry,the residue was stirred for 20 minutes at room temperature in a mixtureof 140 parts of 1,1'-oxybisethane and 200 parts of water. The mixturewas filtered and the filtrate was extracted with trichloromethane andwater. The separated organic phase was dried, filtered and evaporated.The residue was purified by column over silica gel, first using amixture of dichloromethane and methanol (98:2 by volume) and then amixture of ethyl acetate and cyclohexane (70:30 by volume) as eluents.The pure fractions were collected and the eluent was evaporated. Theresidue was converted into the sulfate salt in 8 parts of 2-propanoneand ethanol at 0° C. The salt was filtered off and crystallized from amixture of 2-propanol and methanol. The product was filtered off anddried, yielding 1.33 parts (5.1%) of6-[(1H-imidazol-1-yl)phenyl-methyl]quinoline sulfate(1:1), monohydrate;mp. 135° C. (compound33).

Example 17

7 Parts of N-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-oxobutanamide wereadded dropwise to 73.6 parts of concentrated sulfuric acid (exothermicreaction, the temperature rose to 90° C.). Upon complete addition, themixture was stirred for 1 hour at 70° C. The reaction mixture was pouredinto crushed ice and the whole was neutralized with an ammoniumhydroxide solution to pH 9. The precipitated product was filtered offand taken up in water. The whole was extracted with dichloromethane. Theaqueous layer was concentrated. The crystallized product was filteredoff, washed with 2-propanone and dried in vacuo at 100° C., yielding2.25 parts (34.8%) of6-(1H-imidazol-1-ylmethyl)-4-methyl-2(1H)-quinolinone; mp. 266.0° C.(compound 1).

Example 18

To a stirred and heated (100° C.) solution of 10 parts of4-(1H-imidazol-1-ylmethyl)benzenamine in 50 parts of poly phosphoricacid were added 15 parts of ethyl 3-oxobutanoate. The whole was stirredfor 4 hours at 140° C. 100 Parts of water were added to the mixture andthe whole was neutralized with potassium carbonate. The product wasextracted with a mixture of ethyl acetate and methanol. The extract wasdried, filtered and concentrated. The concentrate was crystallized froma mixture of 2-propanone and methanol. The product was filtered off anddried, yielding 2 parts (14.4%) of6-(1H-imidazol-1-ylmethyl)-2-methyl-4(1H)-quinolinone; mp. 245.5° C.(decomp.) (compound 77).

Example 19

To a stirred solution of 10.5 parts ofN-[4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]-3-phenyl-2-propenamide in110 parts of chlorobenzene were added 18.5 parts of aluminium chloride.The reaction mixture was stirred for 3 hours at 120° C. After cooling toroom temperature, the product was extracted with ethyl acetate. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture of dichloromethaneand methanol (90:10 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom a mixture of 2-propanone and methanol. The product was filtered offand dried, yielding 1.3 parts (15.4%) of6-[(1H-imidazol-1-yl)phenylmethyl]-2(1H)-quinolinone; mp. 226.9° C.(compound 2).

Example 20

To a stirred solution of 2 parts of sodium in 24 parts of 1-propanol wasadded a solution of 3.2 parts of2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline in 16 parts of1-propanol at room temperature under nitrogen atmosphere. After stirringfor 2 hours at reflux temperature, the mixture was evaporated. Theresidue was taken up in a potassium carbonate solution and the productwas extracted with ethyl acetate. The extract was dried, filtered andevaporated. The residue was purified by column chromatograhpy oversilica gel using a mixture of dichloromethane and methanol (98:2 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from 2-propanone. The productwas filtered off and dried, yielding 1.8 parts (31.9%) of6-(1H-imidazol-1-ylmethyl)-4-methyl-2-propoxyquinoline; mp. 137.9° C.(compound 35).

Example 21

A solution of 13 parts of6-(1H-imidazol-1-ylmethyl)-4-methyl-2(1H)-quinolinone in 55 parts ofphosphoryl chloride was stirred for 1 hour at room temperature. Afterevaporation, the residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol (95:5 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from a mixture of acetonitrileand 2,2'-oxybispropane. The product was filtered off and dried, yielding1.75 parts (12.5%) of2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline; mp. 120.6° C.(compound 34).

All the other compounds listed in tables 5-9 were obtained by analogousmethods of preparation as described in examples 12-21, the actual methodof preparation being indicated in column 2 (Ex. No.).

                                      TABLE 5                                     __________________________________________________________________________     ##STR33##                                                                    Comp.                                                                             Ex.                                                                       No. No.                                                                              R X.sup.1 X.sup.2                                                                       Y       p R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                           mp./salt                                 __________________________________________________________________________    1   17 H CHCH    H       6 H  H  CH.sub.3                                                                            266.0                                  2   19 H CHCH    C.sub.6 H.sub.5                                                                       6 H  H  H     226.9                                  3   17 H CHCH    C.sub.6 H.sub.5                                                                       6 H  H  CH.sub.3                                                                            209.3                                  4   17 H CHCH    4-FC.sub.6 H.sub.4                                                                    6 H  H  CH.sub.3                                                                            215.6                                  5   17 H CHCH    4-ClC.sub.6 H.sub.4                                                                   6 H  H  CH.sub.3                                                                            137.6/0.5H.sub.2 O                     6   17 H CHCH    3-ClC.sub.6 H.sub.4                                                                   6 H  H  CH.sub.3                                                                            164.3/0.5H.sub.2 O                     7   17 H CHCH    3-FC.sub.6 H.sub.4                                                                    6 H  H  CH.sub.3                                                                            192.9                                  8   19 H CHCH    i-C.sub.3 H.sub.7                                                                     6 H  H  H     165.7                                  9   19 H CHCH    4-ClC.sub.6 H.sub.4                                                                   6 H  H  H     180.1                                  10  19 H CHCH    3-ClC.sub.6 H.sub.4                                                                   6 H  H  H     212.2                                  11  19 H CHCH    3-FC.sub.6 H.sub.4                                                                    6 H  H  H     210.6                                  12  19 H CHCH    4-FC.sub.6 H.sub.4                                                                    6 H  H  H     253.7                                  13  14 H NCH     H       6 H  H  H   >300/H.sub.2 O                           14  19 H CHCH    H       6 H  H  H     229.6                                  __________________________________________________________________________

In the previous and following tables p indicates the position of the1H-azol-1-ylmethyl moiety on the quinoline ring.

                                      TABLE 6                                     __________________________________________________________________________     ##STR34##                                                                    Comp.                                                                             Ex.                                                                       No. No.                                                                              R X.sup.1 X.sup.2                                                                       Y       p R.sup.4                                                                          R.sup.5                                                                           R.sup.6                                                                           mp./salt                                __________________________________________________________________________    15  15 H CHN     C.sub.6 H.sub.5                                                                       6 H  H   H   220.1                                   16  15 H CHCH    C.sub.6 H.sub.5                                                                       6 H  H   H   223.9                                   17  15 H NCH     C.sub.6 H.sub.5                                                                       6 H  H   H   187.8                                   18  15 H NCH     3-ClC.sub.6 H.sub.4                                                                   6 H  H   H   170.6/HNO.sub.3                         19  15 H CHN     3-ClC.sub.6 H.sub.4                                                                   6 H  H   H   110.1/HNO.sub.3                         20  15 H CHCH    3-ClC.sub.6 H.sub.4                                                                   6 H  H   H   189.5                                   21  15 H CHCH    CH.sub.3                                                                              6 H  H   H   184.8                                   22  15 H CHN     CH.sub.3                                                                              6 H  H   H   172.3                                   23  15 H NCH     CH.sub.3                                                                              6 H  H   H   220.3                                   24  16 H CHCH    c-C.sub.3 H.sub.5                                                                     6 H  H   H   168.7                                   25  -- H CHCH    i.C.sub.3 H.sub.7                                                                     6 H  H   H   --                                      26  -- H NCH     i.C.sub.3 H.sub.7                                                                     6 H  H   H   --                                      27  -- H CHN     i.C.sub.3 H.sub.7                                                                     6 H  H   H   --                                      28  -- H CHCH    3-ClC.sub.6 H.sub.4                                                                   6 H  CH.sub.3                                                                          CH.sub.3                                                                          --                                      __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________     ##STR35##                                                                    Comp.                                                                             Ex.                                                                       No. No.                                                                              R  X.sup.1 X.sup.2                                                                       Y          p R.sup.7                                                                              R.sup.8                                                                         R.sup.9                                                                            mp./salt                         __________________________________________________________________________    29  13 H  CHCH    H          6 H      H H    254.6/2 HCl                      30  13 H  CHCH    H          8 H      H H    167.8/(COOH).sub.2               31  13 H  CHCH    H          7 H      H H    163.8/2(COOH).sub.2              32  13 H  CHCH    H          5 H      H H    216.4/0.5(COOH).sub.2            33  16 H  CHCH    C.sub.6 H.sub.5                                                                          6 H      H H     79.8/H.sub.2 SO.sub.4                                                        /H.sub.2 O                       34  21 H  CHCH    H          6 Cl     H CH.sub.3                                                                           120.6                            35  20 H  CHCH    H          6 C.sub.3 H.sub.7 O                                                                    H CH.sub.3                                                                           137.9                            36  12 H  CHCH    C.sub.6 H.sub.5                                                                          7 H      H H    110.7                            37  20 H  CHCH    H          6 i-C.sub.3 H.sub.7 O                                                                  H CH.sub.3                                                                           111.1                            38  20 H  CHCH    H          6 CH.sub.3 O                                                                           H CH.sub.3                                                                           142.6                            39  21 H  CHCH    H          6 CH.sub.3                                                                             H Cl   103.7                            40  20 H  CHCH    H          6 CH.sub.3                                                                             H CH.sub.3 O                                                                         116.9                            41  14 H  CHCH    3-ClC.sub.6 H.sub.4                                                                      6 H      H H    120.7                            42  14 H  CHCH    3-FC.sub.6 H.sub.4                                                                       6 H      H H     98.9                            43  14 H  NCH     C.sub.6 H.sub.5                                                                          6 H      H H    173.2                            44  14 H  CHN     C.sub.6 H.sub.5                                                                          6 H      H H    115.0/H.sub.2 0/HCl              45  14 H  NCH     4-ClC.sub.6 H.sub.4                                                                      6 H      H H     87.8/0.5H.sub.2 O               46  14 H  CHN     3-ClC.sub.6 H.sub.4                                                                      6 H      H H    120.7                            47  14 H  CHCH    3-CH.sub.3 C.sub.6 H.sub.4                                                               6 H      H H    124.7                            48  14 H  CHN     4-ClC.sub.6 H.sub.4                                                                      6 H      H H    201.8/HCl/0.5H.sub.2 0           49  14 H  CHCH    3-CH.sub.3 OC.sub.6 H.sub.4                                                              6 H      H H    121.3                            50  14 H  NCH     3-ClC.sub.6 H.sub.4                                                                      6 H      H H    161.1                            51  14 H  CHCH    3,4-F.sub.2 C.sub.6 H.sub.3                                                              6 H      H H    108.5                            52  14 H  CHCH    3,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                     6 H      H H    122.1                            53  14 H  CHN     3,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                     6 H      H H    127.5                            54  16 H  CHCH    1 H-imidazol-1-yl                                                                        6 H      H H    193.8/*                          55  16 H  CHCH    2-thienyl  6 H      H H    124.7                            56  14 H  CHCH    3-CF.sub.3 C.sub.6 H.sub.4                                                               6 H      H H    133.9                            57  14 H  CHCH    4-CH.sub.3 C.sub.6 H.sub.4                                                               6 H      H H    133.9/*                          58  14 H  NCH     3-FC.sub.6 H.sub.4                                                                       6 H      H H    165.0                            59  14 H  CHN     3,4-F.sub.2 C.sub.6 H.sub.3                                                              6 H      H H    104.2                            60  14 H  CHN     4-FC.sub.6 H.sub.4                                                                       6 H      H H    135.1/*                          61  14 H  NCH     3-CH.sub.3 C.sub.6 H.sub.4                                                               6 H      H H    118.0                            62  14 H  CHN     4-CH.sub.3 C.sub.6 H.sub.4                                                               6 H      H H    164.5/*                          63  14 H  CHN     4-OCH.sub.3 C.sub.6 H.sub.4                                                              6 H      H H    151.1/*                          64  14 H  NCH     3-OCH.sub.3 C.sub.6 H.sub.4                                                              6 H      H H    142.0                            65  14 H  NCH     3,4-F.sub.2 C.sub.6 H.sub.3                                                              6 H      H H    149.5                            66  14 H  CHN     3-CF.sub.3 C.sub.6 H.sub.4                                                               6 H      H H    142.9                            67  14 H  CHCH    c.C.sub.6 H.sub.11                                                                       6 H      H H    285.0/2 HCl                      68  14 H  CHN     3-OCH.sub.3 C.sub.6 H.sub.4                                                              6 H      H H    150.0/*                          69  14 CH.sub.3                                                                         CHCH    C.sub.6 H.sub.5                                                                          6 H      H H     52.6/0.5H.sub.2 O               70  14 H  CHN     3-CH.sub.3 C.sub.6 H.sub.4                                                               6 H      H H    117.9                            71  -- H  CHCH    c.C.sub.3 H.sub.5                                                                        6 H      H H     --                              72  -- H  CHCH                                                                                   ##STR36## 6 H      H H     --                              73  -- H  CHCH    CH.sub.3 CHCH                                                                            6 H      H H     --                              74  -- H  CHCH    3-pyridinyl                                                                              6 H      H H     --                              75  -- H  CHN     3,4Cl.sub.2 C.sub.6 H.sub.3                                                              6 H      H H     --                              76  -- H  CHCH    3,4Cl.sub.2 C.sub.6 H.sub.3                                                              6 H      H H     --                              __________________________________________________________________________     * = (COOH).sub.2                                                         

                                      TABLE 8                                     __________________________________________________________________________     ##STR37##                                                                    Comp.                                                                             Ex.                                                                       No. No.                                                                              R X.sup.1 X.sup.2                                                                       Y  p R.sup.10                                                                         R.sup.11                                                                          R.sup.12                                                                          mp./salt                                     __________________________________________________________________________    77  18 H CHCH    H  6 H  CH.sub.3                                                                          H   245.5 (decomp)                               __________________________________________________________________________

C. Pharmacological Examples

The useful pharmacological properties of the compounds of the presentinvention can for example be demonstrated by the following experiment.

Example 22 Metabolism of Exogenously Administered all-trans-retinoicAcid

Male Wistar rats weighing 200˜210 g were orally treated with vehicle(PEG 200) or with 40 mg/kg of a compound of formula (I). One hour later,the animals were anesthetized with ether and injected intrajugularlywith 0.50 ml saline solution containing 20 μg of all-trans-retinoicacid. Two hours after this injection, rats were killed by decapitationand blood was collected on heparin. Blood samples were centrifuged (1000g, 15 min) and plasma was recovered to determine the quantity ofplasmatic all-trans-retinoic acid. The samples were analyzed by means ofHPLC with UV-detection at 350 nm. Quantification was achieved by peakarea integration and external standardization. Under the conditionsused, plasma concentrations of the retinoic acid in vehicle-pretreatedanimals were not detectable (<0.5 ng/ml), whereas compound nos. 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 20, 21, 24, 33, 41, 42, 55 and 67enhanced the recovery of all-trans-retinoic acid from the plasma to atleast 10 ng/ml after dosing with 40 mg/kg.

Example 23 Metabolism of Endogenously Administered all-trans-retinoicAcid

Male Wistar rats weighing 200˜210 g were orally treated with vehicle(PEG 200) or with 40 mg/kg of a compound of formula (I). Two hours afterdrug administration, the rats were killed by decapitation and blood wascollected on heparin. Blood samples were centrifuged (1000 g, 15 min)and plasma was recovered to determine the quantity of plasmaticall-trans-retinoic acid. The samples were analyzed by means of HPLC withUV-detection at 350 nm. Quantification was achieved by peak areaintegration and external standardization. Under the conditions used,plasma concentrations of the retinoic acid in vehicle-pretreated animalswere not detectable (<0.5 ng/ml), whereas compound nos. 2, 3, 4, 7, 8,11, 12, 16, 19, 20, 24, 33, 41, 42, 46, 48, 49, 51, 55, 56, 59, 60, 66,67, 68, 69 and 70 enhanced the recovery of all-trans-retinoic acid fromthe plasma to at least 1 ng/ml.

We claim:
 1. A method of treating mammals suffering from disorders whichare characterized by an increased proliferation or abnormaldifferentiation of cells by the systemic or topical administration tosaid mammals of an effective amount of a compound of the formula:##STR38## a pharmaceutically acceptable acid addition salt thereof or astereochemically isomeric form thereof, wherein:--X¹ ═X² -- represents abivalent radical of formula

    --CH═CH--                                              (x),

    --CH═N--                                               (y),

    or

    --N═CH--                                               (z);

R represents hydrogen or C₁₋₆ alkyl; Y represents hydrogen, C₁₋₁₀ alkyl,C₃₋₇ cycloalkyl, Ar¹, Ar² --C₁₋₆ -alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl;and Z represents a radical of the formula: ##STR39## wherein: R¹ and R⁴each independently represent hydrogen, C₁₋₆ alkyl or Ar² C₁₋₆ alkyl; R²and R⁵ each independently represent hydrogen, C₁₋₆ alkyl or Ar² ; and R³and R⁶ each independently represent hydrogen or C₁₋₆ alkyl, and whereinin the foregoing: Ar¹ represents phenyl, substituted phenyl,naphthalenyl, pyridinyl, imidazolyl, triazolyl, thienyl, furanyl orthiazolyl, and Ar² represents phenyl or substituted phenyl, wherein saidsubstituted phenyl in Ar¹ or Ar² represents phenyl substituted with 1, 2or 3 substituents each independently selected from the group consistingof halo, hydroxy, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, cyano,amino, mono- and di(C₁₋₆ alkyl)amino, nitro, carboxyl, formyl and C₁₋₆alkyloxycarbonyl.
 2. A method according to claim 1 wherein R is hydrogenor C₁₋₄ alkyl; Y is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl,substituted phenyl, pyridinyl, imidazolyl or thienyl and R¹, R², R³, R⁴,R⁵ and R⁶ each independently are hydrogen or C₁₋₄ alkyl.
 3. A methodaccording to claim 2 wherein --X¹ ═X² -- is a radical of formula (x) or(y); and Y is hydrogen, C₁₋₄ alkyl, cyclopropyl, cyclopentyl,cyclohexyl, imidazolyl, pyridinyl, thienyl or phenyl optionallysubstituted with one or two substituents each independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy and trifluoromethyl.
 4. A methodaccording to claim 3 wherein:Z is a radical of formula (a-1) wherein R¹and R² are hydrogen, R³ is hydrogen or C₁₋₄ alkyl and Y is hydrogen,C₁₋₄ alkyl or phenyl optionally substituted with one or two halo atoms;or Z is a radical of formula (a-2) wherein R⁴, R⁵ and R⁶ all arehydrogen, and Y is hydrogen, C₁₋₄ alkyl, cyclopropyl or phenyloptionally substituted with one or two halo atoms.
 5. A method accordingto claim 1 wherein Z is a radical of formula (a-1); R is hydrogen; --X¹═X² -- is a radical of formula (x) or (y); Y is isopropyl, phenyl orhalophenyl; R¹ and R² are both hydrogen; and R³ is methyl.
 6. A methodaccording to claim 1 wherein Z is a radical of formula (a-2); R ishydrogen; --X¹ ═X² -- is a radical of formula (x) or (y); Y iscyclopropyl, phenyl or halophenyl; and R⁴, R⁵ and R⁶ are all hydrogen.7. A method according to claim 1 wherein the compound is6-[(4-fluorophenyl) (1H-imidazol-1-yl)methyl]-2(1H)-quinolinone, apharmaceutically acceptable acid addition salts or a possiblestereoisomeric form thereof.
 8. A method according to claim 1 whereinthe compound is 6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-3,4-dihydro-2(1H)-quinolinone, apharmaceutically acceptable acid addition salt or a possiblestereoisomer thereof.
 9. A method according to claim 1 wherein thecompound is3,4-dihydro-6-[(1H-imidazol-1-yl)phenylmethyl]-2(1H)-quinolinone, apharmaceutically acceptable acid addition salt or a possiblestereoisomer thereof.